The Rare360 Editorial Team

Sep 613 min read

Battling Batten Disease: A Fight Against the Rare and Relentless

An image of the child with Batten Disease and their two parents in a comforting home environment.

Batten disease is a rare and devastating neurodegenerative disorder that primarily affects children, leading to severe neurological impairment and, ultimately, a shortened life expectancy. As one of the most common forms of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), Batten disease is characterized by the accumulation of fatty substances called lipopigments in the body's cells, leading to progressive damage to the nervous system.

The onset of Batten disease typically occurs in childhood, with initial symptoms often mistaken for less serious conditions. These early signs, such as vision problems, seizures, and cognitive decline, can quickly progress to more severe neurological impairments, including loss of motor skills and speech, blindness, and dementia. Despite its rarity, Batten disease presents significant challenges not only to the patients but also to their families and caregivers, who must navigate the complexities of managing a chronic, progressive illness.

Causes of Batten Disease

Batten disease can be caused by genetic mutations in any of more than a dozen known genes, collectively referred to as CLN genes (CLN1, CLN2, etc). These specific genes are responsible for producing enzymes required to break down cellular waste in the lysosomes, which are compartments within cells that digest and recycle various substances. When these enzymes are deficient or dysfunctional due to genetic mutations, waste products accumulate within the cells, particularly in neurons, leading to progressive damage.

The disease is inherited in an autosomal recessive pattern, meaning that a child must inherit two copies of the mutated gene, one from each parent, to develop the condition. Parents who carry one copy of the mutated gene are usually asymptomatic but have a 25% chance with each pregnancy of having a child with Batten disease. Siblings of affected children have a one in four chance of also developing the disease, and a 50 percent chance of being a carrier.

Prevalence of Batten Disease

Batten disease is an extremely rare disorder, with an estimated prevalence of around 20,000 to 30,000 people worldwide .

Batten disease affects populations across the globe, but there are notable variations in incidence based on geographic and ethnic factors. Higher prevalence rates have been observed in certain regions of Northern Europe, particularly in Scandinavian countries such as Finland and Norway. In these regions, the incidence of Juvenile NCL (JNCL) can be as high as 7 per 100,000 live births.

In the United States and Canada, Batten disease is rare, with an incidence consistent with global averages. The United States has roughly 2 to 4 cases per 100,000 live births annually.

Types of Batten Disease

Batten disease refers specifically to the 13 recognized types). Each type is categorized as 'ceroid lipofuscinosis, neuronal' (CLN) and is assigned a distinct number to represent the specific subtype (e.g., CLN1, CLN2, CLN3, etc.). These forms of Batten disease, which are linked to different genetic mutations, vary in terms of severity, typical age of onset, and rate of progression. The primary types include:

Infantile Batten disease (CLN1)

Infantile Batten disease, also known as CLN1 disease or Santavuori-Haltia disease, is a rare condition that begins in early childhood. It is caused by a mutation in the CLN1 gene, which is responsible for producing an enzyme called palmitoyl-protein thioesterase 1 (PPT1). This enzyme helps the body break down certain proteins and lipids, but in children with this mutation, a deficiency of PPT1 leads to the buildup of these substances inside cells, particularly in the brain. As a result, the normal functioning of neurons and other cells is impaired, leading to a cascade of symptoms.

Typically, CLN1 begins to show signs between 2 months and 2 years of age. Early on, children may fail to reach key developmental milestones, such as walking or talking, and their cognitive and motor skills begin to lag. What initially seems like normal development is soon overshadowed by sudden jerking movements, seizures, and decreased muscle tone. As time passes, developmental progress halts, and parents may notice their child becoming restless, irritable, or struggling to sleep through the night.

Children with CLN 1 (also termed Infantile Batten disease) may start to lose previously acquired skills, such as standing, walking, or talking. They might also develop repetitive hand movements and a general "floppiness" in their body, reflecting the rapid decline in muscle tone. As they enter their toddler years, they become increasingly dependent on caregivers. Seizures become more frequent, and vision progressively deteriorates until they are no longer able to see.

By the age of three, most children are fully dependent, unable to sit, feed themselves, or even communicate. As their muscles stiffen, they may require a feeding tube and experience frequent chest infections. Tragically, most children with Infantile Batten disease pass away in early to mid-childhood.

Late infantile Batten disease (CLN2)

Late Infantile Batten disease, also known as CLN2 disease or Jansky-Bielschowsky disease, is a rare form of Batten disease that affects young children. It is caused by mutations in the CLN2 gene, which is responsible for producing a vital enzyme called tripeptidyl peptidase 1 (TPP1). Without enough of this enzyme, proteins and lipids build up in brain cells, disrupting normal function and leading to a range of debilitating symptoms. Although CLN2 mutations are most commonly associated with late infantile Batten disease, other gene mutations such as CLN1, CLN5, CLN6, CLN7, and CLN8 can lead to this form as well.

Children with CLN2 disease usually seem healthy and develop normally in their early years. However, by the time they reach their second birthday, subtle signs may start to appear, such as a delay in speech development. The most noticeable early symptom is often epilepsy, with seizures that can range from sudden drop attacks to vacant spells or violent jerking movements. While medication might initially control these seizures, they tend to return and become more challenging to manage over time.

As the disease progresses, children become unsteady on their feet, experiencing frequent falls. Skills like walking, talking, and playing are gradually lost, and by the age of 4 or 5, myoclonic jerks (involuntary muscle twitches) and head nodding become common. This phase is often accompanied by distress, difficulty sleeping, and unexplained periods of agitation. Sadly, vision also deteriorates, and by age 6, most children are fully dependent on caregivers for all aspects of daily life. At this point, a feeding tube may become necessary, and stiffness in the limbs becomes more pronounced. Chest infections are also common as the body becomes more vulnerable. Tragically, untreated children with CLN2 disease typically pass away between the ages of 6 and 12, although in some rare cases, they may live longer.

There is a variant of CLN2 disease where symptoms develop later in childhood, typically around ages 6 or 7, and progress more slowly. These children may first show signs of coordination loss (ataxia), rather than seizures or vision loss, and may survive into their teenage years. In rare instances, a different form of CLN2 disease, known as SCAR7 (spinocerebellar ataxia autosomal recessive 7), presents as ataxia and cerebellar atrophy without the typical seizures or vision loss, making it an unusual but notable variant of this condition.

Juvenile Batten disease (CLN3)

Juvenile Batten disease, also known as CLN3 or Spielmeyer-Vogt-Sjögren-Batten disease, is the most common form of Batten disease. It is caused by mutations in the CLN3 gene, which is responsible for producing a protein called battenin. This condition typically starts to show its effects in children between the ages of 5 and 10, after a few years of seemingly normal development.

The first noticeable symptom is often a gradual loss of vision, usually appearing between the ages of 4 and 7. This vision decline tends to be rapid over the first 6 to 12 months, but children may still have some ability to detect color and light for a while longer.

Around the age of 10, epileptic seizures often begin. These can start with violent jerking movements and loss of consciousness, but may be controlled with medication for months or even years. Over time, however, the seizures usually become harder to manage and may change in nature, evolving into more subtle forms like brief staring spells or periods of confusion accompanied by muddled speech and repetitive movements.

As they enter their teenage years, children with CLN3 often start to have trouble with balance and coordination, leading to more frequent falls. Speech may also become more difficult to understand, and many develop anxiety or worry. Some may even experience hallucinations, hearing voices or seeing things that aren’t real. Gradually, they become more dependent on their families and caregivers for everyday tasks.

Sadly, the disease is life-limiting, with most affected individuals passing away between the ages of 15 and 35, though some do live longer.

Adult Batten disease (CLN1, CLN4, CLN6, CLN13)

Adult Batten Disease can be classified into two types: Type A and Type B.

Type A is linked to defects in the CLN1 or CLN6 genes. People with this form often experience seizures with uncontrollable jerky movements (myoclonus), tics or tremors, poor coordination (ataxia), and difficulties with speech.
Type B, on the other hand, is caused by mutations in the CTSF gene (CLN13) or the DNAJC5 gene (CLN4). This type is marked by behavioral changes and, in some cases, dementia. While some symptoms are similar to those of Type A, people with Type B are less likely to experience speech difficulties or myoclonic seizures.

Symptoms of adult Batten disease usually appear in the patient's 30s but can develop earlier, during adolescence, or as late as after age 50.

Epilepsy with Progressive Mental Retardation (CLN8 variant)

Epilepsy with Progressive Mental Retardation (EPMR), also known as Northern Epilepsy Syndrome, is a milder form of CLN8 disease. The more severe form of CLN8 disease is a variant of late-infantile Batten disease. Both of these conditions are caused by mutations in the CLN8 gene, which normally helps produce a protein important for cell function. When this protein isn’t produced properly, symptoms begin to develop.

In EPMR, the first signs usually appear between the ages of 5 and 10. These include seizures, difficulty with learning and memory, and noticeable changes in behavior. As children approach puberty, the frequency of seizures may increase, but cognitive decline tends to accelerate at this stage. Interestingly, after puberty, the number of seizures often decreases on its own.

Some individuals with EPMR may also lose the ability to speak over time. However, compared to other forms of Batten disease, people with EPMR tend to have a longer life expectancy.

CLN9 Disease

CLN9 disease is a rare form of Batten disease that shares similarities with the juvenile type. While the specific gene responsible hasn't been identified yet, research shows that CLN9-deficient cells have lower levels of sphingolipids—a type of fat molecule that plays a role in cell growth, differentiation, and survival.

Children with CLN9 disease typically begin to show symptoms around the age of 4. These symptoms may include difficulty with coordination (ataxia), seizures that are resistant to medication, gradual vision loss, and cognitive decline.

Congenital Batten Disease (CLN10)

Congenital Batten disease, also referred to as CLN10, represents one of the rarest and most severe forms of Batten disease. This condition stems from a mutation in the CLN10 gene (also known as CTSD), which typically helps the body produce a crucial enzyme called cathepsin D. This enzyme plays a key role in cellular waste processing, but when it’s absent or only partially functional, the body struggles to break down certain proteins, leading to a buildup of waste in cells—especially in the brain.

In its most severe form, symptoms can start appearing before birth or very early in life. Infants affected by CLN10 disease often have microcephaly, or abnormally small heads, a sign of abnormal brain development. Soon after birth, they experience severe seizures and episodes of apnea, making survival beyond the first few weeks incredibly challenging.However, not all cases progress at the same pace. If some enzyme function remains, the disease may develop more slowly, with symptoms emerging later in childhood. Children with these milder mutations may experience coordination issues, seizures, and a gradual loss of vision. Over time, they begin to lose developmental skills, resembling the progression seen in late-infantile Batten disease.

Symptoms of Batten Disease

The symptoms of Batten Disease generally reflect the loss of function in various parts of the brain and nervous system. While the exact symptoms can vary depending on the type of Batten disease, some common symptoms across the different forms include:

Seizures: Often one of the earliest signs, particularly in the Late Infantile and Juvenile forms of the disease. Seizures can vary in type and frequency and may become increasingly difficult to control as the disease progresses.
Vision Problems: Vision loss is a hallmark symptom, particularly in Juvenile and Adult forms of Batten disease. This typically begins with night blindness and loss of peripheral vision and can progress to complete blindness.
Cognitive Decline: Progressive intellectual and cognitive impairment is common. This may manifest as difficulty with speech, memory loss, trouble with concentration, and a general decline in mental abilities.
Motor Function Impairments: Loss of motor skills, such as difficulty walking, balancing, and coordinating movements, is a significant symptom. Over time, patients may lose the ability to walk or move independently.
Behavioral Changes: Behavioral and personality changes can occur, including irritability, anxiety, depression, and increased difficulty in managing emotions.
Speech and Communication Difficulties: As the disease progresses, patients may experience challenges with speech, eventually leading to loss of verbal communication abilities.
Muscle Weakness and Wasting: Progressive muscle weakness and wasting are common, leading to reduced mobility and increased reliance on assistive devices.
Sleep Disturbances: Sleep problems, including insomnia and disrupted sleep patterns, are frequent in Batten disease.
Swallowing Difficulties (Dysphagia): As the disease advances, swallowing difficulties may develop, increasing the risk of aspiration and respiratory complications.

Because Batten disease is rare and its symptoms overlap with more common conditions, it is often misdiagnosed in the early stages. Understanding these early warning signs can help in seeking timely medical advice and support.

Diagnosing Batten Disease

Batten Disease is diagnosed through a combination of clinical evaluation, genetic testing, and specialized laboratory tests. Given the rarity and complexity of the disease, a thorough and multidisciplinary approach is typically required to reach a definitive diagnosis.

Clinical Evaluation:
- Initial Assessment: The diagnostic process often begins with a detailed medical history and a thorough physical and neurological examination. Physicians will look for signs such as vision problems, cognitive decline, and motor difficulties, which can be indicative of Batten disease.
Ophthalmological Examination:
- Eye Exam: Since vision loss is a prominent feature of many forms of Batten disease, an ophthalmologist may conduct a comprehensive eye exam, including tests for visual acuity, peripheral vision, and retinal function.
- Electroretinography (ERG): This test measures the electrical responses of the eye's light-sensitive cells (rods and cones) and can help detect retinal dysfunction, which is common in Batten disease.
Genetic Testing:
- DNA Analysis: Genetic testing is crucial for diagnosing Batten disease. This involves analyzing a blood or saliva sample to identify mutations in specific genes known to be associated with the various types of Batten disease, such as CLN1, CLN2, CLN3, and others.
- Carrier Testing: For families with a history of Batten disease, carrier testing can identify individuals who carry the gene mutations responsible for the condition, even if they do not have symptoms.
Enzyme Activity Tests:
- Blood or Skin Samples: In some forms of Batten disease, specific enzyme deficiencies are present. For example, in CLN1 disease, there is a deficiency in the enzyme palmitoyl-protein thioesterase 1 (PPT1). Testing for enzyme activity in blood or skin cells can help confirm the diagnosis.
Neuroimaging:
- MRI and CT Scans: These imaging techniques can reveal structural changes in the brain, such as atrophy (shrinking of brain tissue) and the accumulation of lipofuscins (abnormal deposits in brain cells), which are indicative of Batten disease.
Electroencephalography (EEG):
- Seizure Monitoring: EEG is used to monitor brain activity and can help detect abnormal electrical patterns associated with seizures, which are common in Batten disease.
Biopsy:
- Skin or Muscle Biopsy: In some cases, a biopsy may be performed to examine the presence of characteristic storage materials in cells under a microscope. This can help in confirming the diagnosis of Batten disease.

Studies and patient reports suggest that there can be significant delays in diagnosing Batten disease, often ranging from months to years. These delays are primarily due to the rarity of the disease, the nonspecific nature of early symptoms, and the challenges in clinically differentiating Batten disease from other conditions.

Treatment Options for Batten Disease

Currently, there is no cure for Batten disease, but various treatments are available to manage symptoms, slow disease progression, and improve the quality of life for affected individuals. Research is ongoing, and there have been significant advancements in understanding and potentially treating Batten disease.

Symptomatic Treatment

Anticonvulsant Medications: Seizures are a common symptom in Batten disease, and anticonvulsant medications can help manage and reduce seizure frequency and severity. Medications such as valproic acid, levetiracetam, and lamotrigine are often prescribed.
Physical and Occupational Therapy: These therapies help maintain mobility, strength, and coordination for as long as possible, aiding patients in performing daily activities. Tailored exercise programs, mobility aids, and adaptive equipment are often suggested for people living with Batten disease.
Vision Support: Since vision loss is a hallmark of many forms of Batten disease, visual aids and adaptive techniques can help patients cope with declining vision. This may include specialized eyewear, training in the use of assistive devices, and orientation and mobility training.
Speech and Communication Therapy: Speech therapy can help patients maintain communication skills, and augmentative and alternative communication (AAC) devices can be introduced as needed.
Nutritional Support: As swallowing difficulties and feeding issues develop, nutritional support becomes essential to maintain adequate nutrition and hydration.
Behavioral and Psychological Support: To address the emotional and psychological impact of Batten disease, counselling and behavioural therapies are often suggested for both patients and their caregivers.

FDA-Approved Treatments

Cerliponase Alfa (Brineura): In 2017, the U.S. Food and Drug Administration (FDA) approved Cerliponase Alfa (Brineura) as the first treatment for CLN2 disease, a form of Batten Disease Brineura is an enzyme replacement therapy that delivers a recombinant form of the TPP1 enzyme directly into the brain's cerebrospinal fluid through an intraventricular infusion. This treatment has been shown to help slow the progression of neurological symptoms in patients with CLN2 disease.

Investigational Therapies and Clinical Developments

Gene Therapy: Gene therapy is a promising area of research for Batten disease. The goal is to deliver a functional copy of the defective gene directly into the brain or nervous system, potentially slowing or halting disease progression. Several gene therapy clinical trials are ongoing, including those targeting CLN2, CLN3, and other forms of Batten disease. These trials involve the use of viral vectors to deliver the therapeutic gene to affected cells.
Stem Cell Therapy: Stem cell therapy involves transplanting healthy cells into the brain to replace or repair damaged neurons. Research is ongoing to determine the effectiveness and safety of this approach for Batten disease. Early-phase clinical trials are exploring the use of neural stem cells to treat Batten disease, with the aim of restoring lost brain function.
Small Molecule Therapies: Small molecules that can cross the blood-brain barrier and modulate the disease process are under investigation. These therapies aim to reduce the accumulation of toxic substances in the brain cells of Batten disease patients. Clinical trials are testing various small molecules that could help reduce oxidative stress, inflammation, and the buildup of lipofuscins in the brain.
Enzyme Replacement Therapies: Beyond Brineura, other enzyme replacement therapies are being developed to treat different forms of Batten disease. These therapies aim to replace the deficient enzymes that cause the buildup of toxic substances in the brain. Research is ongoing to develop enzyme replacement therapies for forms of Batten disease other than CLN2.

Conclusion

The Batten disease advocacy landscape is an active rare disease community-based environment filled with persistent parent advocates and activists dedicated to solving Batten disease. While there are several foundations dedicated to supporting individuals and families affected by Batten disease, as well as funding research and raising awareness, the following are some of the prominent organizations:

In the face of Batten disease, a condition as devastating as it is rare, the resolve of patient advocates and activists shine as a beacon of hope. United by a steadfast dedication to finding a cure, this rare disease community channels every resource, every bit of knowledge, and every ounce of energy towards breakthroughs that one day might turn the tide against this relentless disorder. Yet, as the search for a cure presses forward, we must not forget the immediate needs of the families caught in the storm today. Their journey is arduous and their burdens heavy; they deserve our unwavering support and compassion. Together, we can continue to work towards lighting the path to a brighter future while ensuring no one has to walk it alone.